Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Department of Cell Biology, Albert Einstein College of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Department of Toxicology, Faculty of Veterinary Medicine, Okayama University of Science, Imabari-shi, Ehime, Japan.
Biochem Biophys Res Commun. 2022 Dec 25;636(Pt 1):205-212. doi: 10.1016/j.bbrc.2022.10.085. Epub 2022 Oct 28.
The placenta plays various roles in a healthy pregnancy, and abnormalities in the placenta result in adverse outcomes. Adequate differentiation of trophoblast subtypes is necessary for placental function, but the molecular mechanisms that determine trophoblast cell fate remain unclear. Here, we screened small molecular compound (SMC) libraries (1904 SMCs) to identify particular SMCs which regulate trophoblast differentiation in mouse trophoblast stem cells (mTSCs) to understand the molecular mechanisms underlying cell fate decision in trophoblast cells. The two-step screening revealed a novel effect of N-oleoyldopamine (OLDA), an endogenic vanilloid, to promote differentiation into parietal trophoblast giant cells (P-TGCs) and repress them into spongiotrophoblast cells in mTSCs. Analyses by gene deletion and inhibitor treatments indicated that transient receptor potential cation channel subfamily V member 3 (Trpv3), one of the candidates for targeting by OLDA, was involved in maintaining stem status and P-TGC differentiation in mTSCs. Finally, transcriptome analysis revealed that Fosl1, a key regulatory factor in differentiation into P-TGCs, was upregulated by OLDA treatment, suggesting that OLDA promoted the differentiation of mTSCs into P-TGCs via regulation of Fosl1 expression.
胎盘在健康妊娠中发挥着各种作用，而胎盘异常会导致不良后果。滋养细胞亚型的充分分化对于胎盘功能是必要的，但决定滋养细胞命运的分子机制仍不清楚。在这里，我们筛选了小分子化合物（SMC）文库（1904 种 SMC），以鉴定特定的 SMC，调节小鼠滋养层干细胞（mTSC）中的滋养层分化，以了解滋养细胞中细胞命运决定的分子机制。两步筛选揭示了内源性香草醛 N-油酰基多巴胺（OLDA）促进壁细胞滋养层巨细胞（P-TGC）分化并抑制其向绒毛滋养层细胞分化的新作用。通过基因缺失和抑制剂处理分析表明，瞬时受体电位阳离子通道亚家族 V 成员 3（Trpv3）是 OLDA 作用的候选靶标之一，参与维持 mTSC 中的干细胞状态和 P-TGC 分化。最后，转录组分析显示，Fosl1 是 P-TGC 分化的关键调节因子，被 OLDA 处理上调，提示 OLDA 通过调节 Fosl1 的表达促进 mTSC 分化为 P-TGC。
